Tetracycline compounds are widely used in therapy primarily for their antimicrobial effect. A preferred family of such agents comprises the 7- or 9-alkylamino-6-deoxy-6-demethyltetracyclines, including the non-toxic acid-addition salts thereof. Commonly assigned Boothe et al, U.S. Pat. No. 3,148,212, and Petisi et al, U.S. Pat. No. 3,226,436, describe the preparation of this family of tetracycline compounds. Although they have achieved widespread use in oral dosage forms, particularly 7-dimethylamino-6-deoxy-6-demethyltetracycline hydrochloride, also known as minocycline hydrochloride, they have one drawback, and that is a tendency to cause CNS and gastrointestinal side effects including lightheadedness, dizziness, vertigo, nausea, vomiting and diarrhea. People on oral therapy with these drugs must, as a result, be cautioned about driving vehicles or using hazardous machinery, and also lowered patient compliance in continuing to take the drug naturally occurs.
In Bechgaard, U.S. Pat. No. 4,606,909, the placement of a sparingly soluble active substance, such as tetracycline, in an oral controlled relese dosage form is disclosed. The spraingly soluble active substance must be used with a dispersion-enhancing substance, such as an anionic detergent to promote solubility in intestinal fluids. The composition is formed into small spheres and enteric coated to eliminate any release of drug in the stomach. The coated spheres are tabletted or loaded into capsules. There is no teaching that such a dosage form can be used to avoid dizziness and/or nausea associated with tetracycline therapy. Moveover the requirement to use a dispersion-enhancing substance, especially an anionic detergent, is a negative factor.
McAinsh et al, U.S. Pat. No. 4,138,475, disclose that propranolol or a pharmaceutically-acceptable salt thereof can be formulated into a sustained release pharmaceutical composition by mixing with a non-water-swellable microcrystalline cellulose and forming into spheroids. These spheres are coated with a heavy film of hydroxypropyl methylcellulose and/or a plasticizer to eliminate any release of the drug in the stomach. The film coated spheroids are then filled into gelatin capsules. Apart from the fact that propranolol is used as a beta-blocker to treat heart problems and not for oral antimicrobial use, the dosage form of the McAinsh patent is primarily adapted, like all sustained release dosage forms, to reduce the total number of capsules needed for a daily dose. Propranol is often taken 3 to 4 times daily, whereas most recent oral tetracyclines are given once or twice a day. Furthermore, there is no hint or suggestion in McAinsh et al that the pharmaceutical compositions should be used with tetracycline compounds. Finally, there is no mentioned whatsoever that such dosage forms can be used with propranolol, or for that matter, with any other drug, to overcome adverse reactions, especially CNS and gastrointestinal side effects.
Parke-Davis has recently offered for use by the medical profession capsules under the trademark DORYX.RTM. containing specially coated pellets of doxycycline hyclate for oral administration. See, Physicians Desk Reference, 1987, Medical Economics Company, Oradell, NJ, pages 1487-1489. In contrast to minocycline hydrochloride, and its isomers and analogs, doxycycline hyclate does not contain an alkyl amino group at either the 7- or the 9-position. The Parke-Davis pellets are said to comprise in addition to the doxycycline compound, lactose, microcrystalline cellulose and povidone (polyvinylpyrrolidone). The film coating is both thick, e.g., 15-20% by weight based on the granules, and necessary. The disclosure in the Physicians Desk Reference is unclear as to the advantages for using such film coated pellets but it is believed that the film is used to minimize release in the stomach and any resulting gastric distress.
To overcome the problems of both CNS and gastric side effects mentioned above, a need still exists for an improved controlled release tetracycline containing composition, especially one without film coatings, particularly, thick film coatings and this has been met by the present invention in a way not suggested by the foregoing prior art. Although spherical granules will be used, they will be specially formulated to control release on oral administration. Preferably, they will release a minor portion of the tetracycline compound slowly in the human stomach and then rapidly release the remainder in the human intestine. This is accomplished by preparing microspheres containing thereon or therein the drug blended with one or more judiciously selected excipients and adapting the spheres to accomplish the controlled release, while omitting any film coating whatsoever or using only an ultra thin layer of polymer film which erodes only slowly in the stomach but very rapidly in the small intesting. While reasons for the attained advantages in reducing side effects are not clearly understood at this time, it is believed that slow release of the tetracycline compound in the stomach avoids gastric upset and rapid release of the remainder of the tetracycline compound in the small intestine can be better tolerated in terms of CNS side effects because there is no extreme elevation in short-term blood levels. Although the full scope of the advantages of this invention is believed to be broadly applicable for tetracycline compounds in general, it appears to be uniquely suitable for use with 7- or 9-alkylamino-6-deoxy-6-demethyltetracycline compounds.